There are large individual differences among humans and animals in behavioral, physiological and toxicological responses to drugs of abuse. Many of these individual differences in behavioral responses to drugs display substantial genetic components. Transgenic animals provide means for approaching several interrelated goals: 1)Ascertainment of biochemical and behavioral consequences of the introduction of or disruption of specific genes; 2)Ascertainment of the consequences of over- or under-expressing candidate genes identified in human studies; 3) Elucidation of gene elements yielding cell-type specific expression and trans-synaptic gene regulation; 4) Studying influences of interactions between variants at different genomic loci; 5)Elucidating haplotype-specific levels of expression differences in vivo, expecially when currently-available cultured cell models are not optimal. Influences of human allelic variations and interactions between dopamine and other systems in mechanisms of reward, reinforcement and learning have led to continuing focus on these systems during this year. In continuing studies of combined transporter and transporter/receptor knockouts, we have obtained novel data concerning the relationship between expression of each of these gene products at normal levels and drug-induced behavioral changes. In studies of variations at candidate gene loci determined from studies of drug-regulated gene expression, we have identified possible effects of cocaine reward in mice with altered levels of expression of KEPIM. We have characterized mice with deletions of an orphan transporter vt-3 and identified its role in uptake of proline and leucine in brain synaptosomes, as well as the ability of other uptake systems to compensate for any effects of its constutuitive deletion on a variety of behaviors. In other single gene knockout experiments, we have reported effects of OPRM1 on body weight, alcohol-induced neurotransmitter changes, effects of opiate drugs and hippocampal neurogenesis. In DAT and/or VMAT2 deleted mice we have identified differential effects on lethality, DAT expression, locomotion and sensitization.